One of the feared—and potentially fatal—complications of ocular melanoma is when the disease metastasizes from the primary site to the liver, and this can occur in a majority of patients. Researchers at the National Cancer Institute are conducting a randomized, Phase III multicenter study in patients with unresectable hepatic metastases secondary to ocular melanoma using a promising new approach using isolated hepatic perfusion with melphalan followed by temozolomide.

About 2,500 people are diagnosed every year in the United States, according to the Ocular Melanoma Foundation. No effective treatment exists for metastatic ocular melanoma. "For patients with metastic ocular melanoma the majority of those who recur—and about 50 to 60 percent of patients—are limited to the liver or have liver predominance," says James F. Pingpank, MD, principal investigator of the study and head of the Surgical Metabolism Section at the National Cancer Institute, NIH Clinical Center in Bethesda, Md. "The driver of their survival is what is going on in their liver. Unlike other types of tumors that recur in the liver predominantly, there appears to be a very minor set of patients who can have resection."

In this study, researchers are testing the hyperthermic isolated hepatic perfusion (IHP) procedure, which temporarily separates the liver's blood supply from the blood circulating throughout the rest of the body. High concentrations of melphalan are then administered to the liver. Once melphalan treatment is completed, the liver's blood supply is reconnected to the rest of the circulatory system, and patients are treated with temozolomide. "Isolating the liver allows us to deliver a higher dose of melphalan than could be tolerated systemically," says Dr. Pingpank.

For the trial, patients will be randomly assigned to receive treatments with melphalan infused into the hepatic artery over 30 minutes via the Delcath System (Delcath Systems, New York City) with filtration of the outflow from the hepatic vein through an extra-corporeal circuit, or to a control group providing best alternative care ranging from palliative therapy to regional or systemic therapies with standard or investigational modalities.

In addition to determining the response rate and duration of response in patients for this therapy, investigators are attempting to determine: the pattern of recurrence; the disease-free and overall survival of patients; and the quality of life of patients treated with this regimen. Within eight to 12 weeks after IHP, patients are re-evaluated by MRI. Patients with stable or responding disease receive oral temozolomide once-daily on days one to five. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patients are followed every three months for two years and then every four months thereafter.

The treatment appears to be an advance over the previous open protocol, which required a 10-day hospital stay and could not be repeated. Dr. Pingpank says it is the same drug and the same approach, but the regimen has a two-day hospital stay, and leads to changes in the toxicity and response. In addition, in contrast with the open protocol, the drug appears to affect patients' bone marrow. "In the open arm, we treated 60 patients with ocular melanoma and had about a 60 to 65-percent response rate," he says. "In this trial, we treated half that number and we appear to be seeing the same rate of response. However, we still have relatively low numbers, and there is a little variability of response. I feel comfortable that we're getting the same range of efficacy. Whether it's actually better, only time and more numbers will tell."

 

Trial Shows Good Results for Ista Allergy Drug

Ista Pharmaceuticals has announced positive results from the preliminary analysis of its second and final Bepreve (bepotastine ophthalmic solution) Phase III clinical study.

The study was designed to evaluate the onset and duration of effect of Bepreve in two concentrations and in two dosing schedules (once-daily and twice-daily) in 130 patients with a history of ocular allergies. Both concentrations demonstrated highly statistically significant reductions in the primary study endpoint of ocular itching and produced highly statistically significant effects on the rapidity of response and in the secondary endpoints measuring additional signs and symptoms of ocular allergy, as well as improvement in total nasal symptoms. No serious ocular adverse events were reported in patients dosed with Bepreve.

ISTA is analyzing the results of an ocular safety study in approximately 850 patients, with preliminary results anticipated before the end of the second quarter of 2008. Once the company completes its analysis of both studies, it expects to file a New Drug Application with the Food and Drug Administration.

 

Older Women with AMD at High Risk of Falls

The University of British Columbia conducted a cross-sectional study in a hospital-based ophthalmology clinic in Vancouver to determine whether older women with exudative age-related macular degeneration are at greater risk of falls than those who do not have the disease.

The study included 115 community-dwelling women aged 70 or older who had exudative AMD (AMD cohort) and two control groups: 54 community-dwelling women without exudative AMD drawn from the same community (non-AMD cohort) and 341 community-dwelling Australian women (Australian normative cohort). Participants were assessed for fall risk using the short-form Physiological Profile Assessment, which provides a fall risk index score and subcomponent measures of vision, proprioception, strength, reaction time and postural sway.

The mean fall risk index score in the AMD cohort (3.20) was significantly greater than that of the non-AMD cohort (1.21), and fall risk scores increased with age to a greater extent in the AMD cohort. The higher fall risk scores in the AMD cohort resulted from significantly worse performance on each PPA test, not just on the test of vision. The AMD cohort also performed worse than the Australian normative cohort in tests of vision, reaction time and postural sway.

The results suggest that older women with AMD have impaired balance, slow visual reaction times and poor vision, which in combination, result in a significantly greater risk of falls than population norms. These deficits are clearly indicated in the physiological falls profile for the group. The authors believe that strategies to enhance balance may be particularly beneficial to prevent falls in this group.

 

Prisms Expand the View for Patients With Hemianopia

Innovative prism glasses can significantly improve the vision and the daily lives of patients with hemianopia, a condition that blinds half the visual field in both eyes. The peripheral prism glasses, which were invented by Eli Peli, OD, a senior scientist at Schepens Eye Research Institute, were evaluated in the first community-based multicenter trial of such a device, which is published in the May issue of the Archives of Ophthalmology. The study was coordinated by Alex Bowers, PhD, a senior scientific associate at the Institute.

"This is the first real breakthrough in the rehabilitation of patients with this condition," says Dr. Peli, the Moakley Scholar in Aging Eye Research at Schepens and a professor of ophthalmology at Harvard Medical School. Dr. Peli had searched for a solution for his hemianopia patients for many years before designing the peripheral prism glasses, creating a prototype in his laboratory.

More than a million Americans suffer from hemianopia, which blinds the vision in one half of the visual field in both eyes, resulting from damage to the optic pathways in the brain. Most commonly caused by strokes, it can also be the result of brain damage from tumors or trauma. A patient with this condition may be unaware of what he or she cannot see and frequently bumps into walls, trips over objects or walks into people on the side where the visual field is missing.

Dr. Peli's goal was to find a way to expand the visual field. He did this by attaching small, specially designed high-power prisms on the top and bottom of one spectacle lens, leaving the center of the lens untouched. The prisms pull in images missing from the visual field above and below the line of sight on the side of the vision loss, and alert the patient to the presence of a potential obstacle or hazard. The patient can then move his/her head and eyes to examine the prism-captured image directly through the clear center of the lens.

Prisms by their nature can shift images from one side of the visual field to the other side (e.g., from the right side of the field to the left side). Before Dr. Peli's invention, others had tried to develop prism glasses to bring the missing part of the patient's visual field into view. However, these previous techniques placed the prisms in the center of the glasses, which resulted in double vision, which is disturbing and confusing. Peli's solution was to keep the central part prism-free and place prisms above and below.

The study reported in Archives evaluated the glasses' ability to improve a patient's walking mobility, which includes obstacle avoidance. Forty-three patients were fitted with prism glasses in 15 community-based clinics around the country. The clinicians interviewed them at six weeks and after 12 months. Success was measured by how many patients continued wearing the prism glasses and by their ranking of the prisms' effectiveness in assisting with obstacle avoidance while walking.

Thirty-two participants (74 percent) continued wearing the glasses at week six. At 12 months, 20 (47 percent) were still donning the spectacles eight hours a day and rating them as "very helpful" for obstacle avoidance. These 12-month-plus patients were reporting significant benefits for a variety of obstacle avoidance scenarios (e.g. walking in crowded areas, unfamiliar places, shopping malls). According to Bowers, the first author of the paper, "These results indicate that the glasses have great promise for helping patients resume normal daily life."

Dr. Peli partnered with a small optical company in Vermont, Chadwick Optical, which funded the study in part through a National Institutes for Health small business grant. Dr. Peli and Karen Keeney, the president of Chadwick Optical, created a permanent version of the prisms with higher optical quality and better durability than the temporary prisms that were fitted at the start of the study. These permanent prisms were provided to 15 of the study patients when they became available.

A new, higher-power version of the permanent prism glasses recently developed by Chadwick Optical should also further expand the visual field and be even more beneficial for patients' mobility, according to Peli. The prototype used in the study expanded the peripheral upper and lower visual fields by 20 degrees without obstructing central vision. The new glasses expand the field by 30 degrees.

A larger community-based, multi-center study is currently under way to evaluate the latest model. In addition to the higher power, the new study is also evaluating a novel design for which Dr. Peli just received a patient from the U.S. patent office.